rs7077757

chr10-110784897-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001134363.3(RBM20):c.1527+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,444,144 control chromosomes in the GnomAD database, including 32,985 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3489 hom., cov: 32)
  • Exomes 𝑓: 0.21 (29496 hom.)
• Consequence: RBM20 NM_001134363.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001230
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.123

Genes affected

RBM20 (HGNC:27424): (RNA binding motif protein 20) This gene encodes a protein that binds RNA and regulates splicing. Mutations in this gene have been associated with familial dilated cardiomyopathy. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-110784897-C-T is Benign according to our data. Variant chr10-110784897-C-T is described in ClinVar as [Benign]. Clinvar id is 43975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-110784897-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RBM20	NM_001134363.3	c.1527+8C>T		splice_region_variant, intron_variant		ENST00000369519.4
RBM20	XM_017016103.3	c.1362+8C>T		splice_region_variant, intron_variant
RBM20	XM_017016104.3	c.1143+8C>T		splice_region_variant, intron_variant
RBM20	XM_047425116.1	c.1143+8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RBM20	ENST00000369519.4	c.1527+8C>T		splice_region_variant, intron_variant		1	NM_001134363.3	P1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31898 AN: 151950 Hom.: 3479 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.0870

Gnomad SAS AF: 0.0997

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.185 AC: 25732 AN: 139300 Hom.: 2596 AF XY: 0.180 AC XY: 13192 AN XY: 73450

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.0828

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.223

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.209 AC: 270142 AN: 1292076 Hom.: 29496 Cov.: 20 AF XY: 0.206 AC XY: 131831 AN XY: 640486

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.0695

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.226

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.197

GnomAD4 genome AF: 0.210 AC: 31939 AN: 152068 Hom.: 3489 Cov.: 32 AF XY: 0.207 AC XY: 15415 AN XY: 74350

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.0866

Gnomad4 SAS AF: 0.0995

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.194

Alfa AF: 0.213 Hom.: 8356

Bravo AF: 0.207

Asia WGS AF: 0.119 AC: 416 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Dilated cardiomyopathy 1DD Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Primary dilated cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	2.6
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs7077757; hg19: chr10-112544655; COSMIC: COSV65707353;